Rickey was born outside of Portsmouth, Ohio, the son of Frank W. and Emily Brown Rickey. He got his start in professional baseball when he spent two seasons in the major leagues as a catcher. Debuting as a St. Louis Brown in 1905, he hit fairly well in 1906 but fielded poorly, which is fatal for a catcher. Sold to the New York Highlanders in 1907, Rickey could neither hit nor field while with the club, and his batting average dropped below .200. One opposing team stole 13 bases while Rickey was behind the plate, setting a record which still stands a century later. Rickey also injured his throwing arm and retired as a player after just one year.

Rickey then spent several years at the University of Michigan as a coach and also earned a law degree. For his undergraduate degree, he attended Ohio Wesleyan University in Delaware, Ohio, where he was a member of Delta Tau Delta.

He returned to the big leagues in 1913, as a front office executive with the Browns. He was responsible for signing young George Sisler. Rickey became the team's manager for the final 12 games of the season, and managed the team for 2 more full seasons. But the Browns finished under .500 both years and no one was surprised when Rickey was fired in 1916 when new ownership took over the club.

Rickey served in the military for a few years, then returned to St. Louis in 1919, this time with the Cardinals, to become team president and manager. His 6+ years as a manager were mediocre, although the team posted winning records from 1921-23 and Rickey wisely invested in several minor league baseball clubs, using them to develop future talent for the Cardinals major league roster.

When Branch Rickey was fired as manager early in the 1925 season, he was 43 years old, had been a player, manager and executive in the Major Leagues and had shown no indication whatsoever that he would ever deserve to belong in the Baseball Hall of Fame.

Rogers Hornsby replaced Rickey to become a player-manager, and in 1926, his first full year as manager, he led the Cardinals to their first World Series championship. Rickey rewarded Hornsby by trading the fiery leader and star second baseman to the New York Giants for Frankie Frisch, who would spend a decade anchoring second for the Cards.

By 1930, Rickey's Cardinals, known as the "Gashouse Gang", were the class of the National League. They won 101 games in 1931 and won the World Series in seven games. The star of the Series that year was rookie Pepper Martin, one of the first Cardinal stars that came from Branch's minor league system. Soon, other minor league graduates joined the team, among them future hall of famers Dizzy Dean and Joe Medwick, and Dean's brother Paul. The Deans and Medwick were integral parts of the 1934 Cardinals, who won a third World Series title.

Kenesaw Mountain Landis was concerned that Rickey's minor league system was going to ruin the game of baseball by destroying most minor league teams, and he twice released over 70 Cardinal minor leaguers in attempts to stop what he perceived to be a cover-up. Despite Judge Landis' best efforts, however, Rickey's minor league system stayed in existence, and similar systems were adopted by every major league team within a few years. Arguably, the farm system saved the minor leagues, by keeping them necessary after the television age began and minor league attendance figures declined.

Rickey continued to develop the Cardinals up until the early 1940s. In his final year at St. Louis, 1942, the Cardinals had their best season in franchise history, winning 106 games and the World Series title. The team was led by a new crop of players developed by the Cardinals, two of whom, Enos Slaughter and Stan Musial, became Hall of Famers; and several others, among them future MVP Marty Marion, who were among the best at their position during their eras. Even their manager Billy Southworth was a product of their farm system.

Rickey was a good friend of Brooklyn Dodgers general manager Larry MacPhail, himself a sound baseball man. MacPhail was drafted into the army to serve in World War II after the 1942 season, and the Dodgers hired Branch Rickey to replace him as President and GM, ending a tenure of over two decades with the Cardinals.

Branch continued being an innovator in his time with Brooklyn. He was responsible for the first full time spring training facility, in Vero Beach, Florida, and encouraged the use of now-commonplace tools such as the batting cage, pitching machines, and batting helmets. While with the Dodgers, his son, Branch Jr., was the team's farm director.

But his most memorable act with the Dodgers involved breaking baseball's color barrier, which had been in place since the mid-1880s, not as a written rule, but merely a policy. This policy had continued under a succession of baseball leaders, including Landis, who was openly opposed to integrating Major League Baseball for what he regarded as legitimate reasons. Landis died in 1944, and that fact along with changing public attitudes presented an opportunity. On August 28, 1945, Rickey signed Jackie Robinson to a minor league contract. October 23, 1945, the signing was announced that Robinson would play with the Dodgers' International League affiliate in Montreal, the Royals, for the 1946 season. He would end up as the league's batting champion, and led the Royals to a dominant league championship.

People noted that Rickey's determination to desegregate Major League Baseball was born out of a combination of idealism and business opportunism. The idealism was at least partially rooted in an early incident in which an African-American player, on an early team with which Rickey worked, was extremely upset at being publicly humiliated at being refused accommodation because of his race in a hotel where the team was bunked. The business element was based on the fact that the Negro Leagues had numerous star athletes, and logically the first Major League team owner to hire them would get first pick of the players at a reasonable price.

Five days before the start of the 1947 season, Rickey purchased Jackie Robinson's contract from the minor leagues. Amid much fanfare, Jackie would debut for the Dodgers on April 15, 1947, becoming the first African-American to play in modern major league baseball. Rickey's "Great Experiment", as it was termed, turned out to be a fantastic success. Robinson was baseball's first rookie of the year, and while he was often jeered by opposing baseball players, managers, and fans, he became extremely popular with the American public. His success became the crowning achievement of Rickey's illustrious career. His Dodgers would make the Series that year, losing in 7 games to the New York Yankees. But Rickey's vision and action had set the stage for the previously mediocre Dodgers to be contenders for decades to come. And it opened the door for other innovative leaders like Bill Veeck of the Cleveland Indians, who integrated the American League soon thereafter.

Rickey continued to run the Dodgers until he resigned in 1950, with owner Walter O'Malley, in some ways, forcing him out. He was not out of a job long, however, as he signed with the Pittsburgh Pirates to become their general manager. Unlike his years with St. Louis and with Brooklyn, his tenure with the Pirates was fairly uneventful all around. The Pirates were a struggling organization that lost 100 games in 3 consecutive years during his tenure, and he stepped down from the team in 1955. It would only be after he left that the Pirates would become contenders again. During his tenure in Pittsburgh, Rickey, along with three other Pittsburgh-area businessmen, funded the incorporation of Fellowship of Christian Athletes, which is now the largest interdenominational school-based Christian sports organization in the United States.

Rickey returned to baseball in 1959, this time as president of a proposed third major league, the Continental League. Major League Baseball was forced to intervene, and made an agreement with Rickey to disband the league in exchange for expansion of the existing leagues.